Source Department of Surgery Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

No effective therapeutic approaches have been available for early recurrences following liver transplantation for hepatocellular carcinoma (HCC). The prognosis for such patients has been poor. We encountered two patients with recurrent HCC following liver transplantation, and in the prescribed sorafenib after the failure of various therapeutic approaches. In vitro experiments have shown sorafenib to be metabolized by the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and glucuronosyltransferase (UGT1A9). The metabolic pathway is predicted to overlap that of calcineurin inhibitors (CNIs). In the two cases in which we used sorafenib, tacrolimus (FK506) was used in case 1 and cyclosporine, in case 2. We therefore have also reported the blood levels of the CNI at the time of sorafenib use. Patients with recurrent HCC following liver transplantation were less tolerant of sorafenib than advanced HCC patients who had not undergone transplantation. Poor tolerance was believed to be due to pharmacological interactions of sorafenib and CNIs. Likewise in our patients, determining blood levels of sorafenib, including the area under the blood concentration-time curve of at least the CNI, in each case allowed us to determine the optimal sorafenib dose for each patient. In the future, when administering sorafenib to treat recurrent liver cancers following liver transplantation, the dose of sorafenib should be started at 200 mg/d and gradually increased while measuring CNI blood levels.